The overall goal of the proposed studies is to continue investigating a novel feature of peroxisome proliferator- activated receptor-3 coactivator-1a (PGC-1a). This gene has been implicated in diabetes, and we recently found that this gene also influences mechanisms associated with Alzheimer's disease (AD) amyloid neuropathology. In the ongoing feasibility studies supporting this Department of Veterans Affairs (VA) Merit application, we found that PGC-1a plays a crucial role in promoting F-box2-E3 ligase (Fbx2) mediated 2-secretase (BACE1) ubiquitination. This role ultimately leads to BACE1 degradation through the ubiquitin proteasome system (UPS). Our findings provide mechanistic evidence that could possibly link PGC-1a to BACE1, which influences AD amyloid neuropathology. The working hypothesis for the studies proposed in this application is that PGC-1a, whose expression is impaired in the AD brain, can synergize Fbx2 and promote ubiquitination that eventually leads to the degradation of BACE1. BACE1 is an attractive target for preventing AD amyloidogenesis because the reduction of BACE1 expression in the brain precludes the generation of amyloidogenic A peptides produced through specific cleavages of the amyloid precursor protein (APP). The present studies were designed to explore the mechanistic role of PGC-1a in the Fbx2 ligase-mediated proteasomal degradation of BACE1. Furthermore, we will explore the functional role of Fbx2 in the attenuation of AD-type amyloid neuropathology and cognitive deterioration in mouse models. Our proposed studies will provide an unprecedented opportunity to explore the mechanistic role of PGC-1a in experimental models of AD-amyloid neuropathology. This will allow us to eventually identify novel approaches to prevent or attenuate AD phenotypes through PGC-1a-mediated responses that could be translated into AD therapies.